Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia

Berger, Andreas; Kofler, Kurt; Bektic, Jasmin; Rogatsch, Hermann; Steiner, Hannes; Bartsch, Georg; Klocker, Helmut

doi:10.1002/pros.10279

Cited by 88 publications

(74 citation statements)

References 41 publications

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“…In addition, increased expression of bFGF has been recently described in stromal cells cultured under hypoxic conditions. 39 Finally, HIF-1␣-dependent alterations of heparan sulfate proteoglycan (HS) composition on the EC surface, which enhance the cell responsiveness to bFGF, has also been demonstrated, 40 further emphasizing the connection between hypoxia, HIF-1␣, and bFGF. 41,42 It remains to be established whether HIF-1-dependent induction of bFGF observed under our experimental conditions is …”

Section: Discussionmentioning

confidence: 99%

Hypoxic induction of an HIF-1α–dependent bFGF autocrine loop drives angiogenesis in human endothelial cells

Calvani

Rapisarda

Uranchimeg

et al. 2006

Blood

219

189

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Hypoxia is a major pathophysiological condition for the induction of angiogenesis, which is a crucial aspect of growth in solid tumors. In mammalian cells, the transcriptional response to oxygen deprivation is largely mediated by hypoxiainducible factor 1 (HIF-1), a heterodimer composed of HIF-1␣ and HIF-1␤ subunits. However, the response of endothelial cells to hypoxia and the specific involvement of HIF-␣ subunits in this process are still poorly understood. We show that human umbilical vein endothelial cells ( IntroductionAngiogenesis is the result of the combined activity of different cellular components of the tumor microenvironment and of signaling molecules that either activate or inhibit neovascularization. 1 Autocrine and paracrine (eg, derived from tumor-and/or stromalinfiltrating cells) production of growth factors promoting angiogenesis ultimately acts on endothelial cells (ECs), which by a process involving invasion of the extracellular matrix, migration, and proliferation gives rise to vessel sprouting and formation of a new vascular bed. In tumor angiogenesis, imbalance between factors promoting and inhibiting vessel formation leads to irregular and disorganized formation of a vascular network, which is nevertheless essential for tumor growth and metastasis. 2,3 Hypoxia is the major pathophysiological condition regulating angiogenesis. Increased angiogenesis in response to hypoxia is part of an adaptive response aimed at achieving increased delivery of oxygen and nutrients to tissues. 4,5 The exposure of ECs to hypoxia has been shown to occur in vivo as a result of structurally abnormal tumor vasculature. 2,6 The transcriptional response of mammalian cells to hypoxia is largely mediated by hypoxia-inducible factor-1 (HIF-1). HIF-1 is a basic helix-loop-helix transcription factor composed of an HIF-1␤ subunit, which is constitutively expressed, and an HIF-␣ subunit, which is strongly up-regulated under hypoxic conditions. 7 At least 3 isoforms of the HIF-␣ subunit have been identified, although HIF-1␣ and HIF-2␣ or EPAS-1 are the ones that appear to play a predominant role in the transcriptional response to hypoxia. In normoxic conditions, HIF-1␣ and HIF-2␣ are degraded by a mechanism involving hydroxylation of 2 prolyl residues, ubiquitylation, and proteasomal degradation through a VHL-dependent pathway. 8,9 Levels of HIF-1␣ are also influenced by genetic alterations, including but not limited to mutations of the VHL gene, growth factors, which increase HIF-1␣ protein synthesis by a pathway involving PI3K/AKT/mTOR and MAPK, and cytokines produced by both tumor and stromal cells. [10][11][12] While HIF-1␣ is ubiquitously expressed, HIF-2␣ was originally identified in ECs and some highly vascularized tissues and hence named endothelial PAS domain protein-1 (EPAS-1). 13,14 However, later studies have shown that HIF-2␣ is also expressed in a variety of other cell types and tissues. [15][16][17][18] The 2 HIF-␣ subunits induce transcriptional activation via interaction with hypoxia response elements (...

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Section: Discussionmentioning

confidence: 99%

Hypoxic induction of an HIF-1α–dependent bFGF autocrine loop drives angiogenesis in human endothelial cells

Calvani

Rapisarda

Uranchimeg

et al. 2006

Blood

219

189

View full text Add to dashboard Cite

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“…FGFs are also found in this gradient pattern and ectopic FGF expression caused abnormal coronary patterning within the ventricular wall (Pennisi and Mikawa, 2005). FGF family members are increased in their expression and secreted under hypoxic conditions in other systems (Berger et al, 2003;Moeller et al, 2004). Many factors important in coronary vessel formation are known to be hypoxia inducible and/or controlled directly or indirectly by HIF-1 in other systems.…”

Section: Regulation Of Cardiac Blood Vessel Developmentmentioning

confidence: 99%

Cardiac Vasculature: Development and Pathology

Watanabe¹,

Wikenheiser²,

Ramírez-Bergeron³

et al. 2011

Vasculogenesis and Angiogenesis - From Embryonic Development to Regenerative Medicine

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“…17,18 Berger et al showed that the production of several growth factors to increase in human prostatic stromal cells by hypoxia, thus playing an important role in the development of prostate hypertrophy. 19 In the present study, we developed a unique culture system to evaluate tumor-stromal cell interaction under hypoxia. Using this system, we analyzed whether hypoxia enhances the invasive activity of pancreatic cancer cells, while also increasing some secretions from fibroblasts, thus leading to the activation of cancer invasion.…”

mentioning

confidence: 99%

Tumor–stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c‐Met pathway

Ide

Kitajima

Miyoshi

et al. 2006

Intl Journal of Cancer

116

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The hypoxic environment in tumor is reported to play an important role in pancreatic cancer progression. The interaction between stromal and cancer cells also contributes to the malignant behavior of pancreatic cancer. In the present study, we investigated whether hypoxic stimulation affects stromal as well as pancreatic cancer cells. Our findings demonstrated that hypoxia remarkably elevated the HIF-1a expression in both pancreatic cancer (PK8) and fibroblast cells (MRC5). Hypoxic stimulation accelerated the invasive activity of PK8 cells, and invasiveness was thus further accelerated when the hypoxic PK8 cells were cultured with conditioned medium prepared from hypoxic MRC5 cells (hypoxic conditioned medium). MMP-2, MMP-7, MT1-MMP and c-Met expressions were increased in PK8 cells under hypoxia. Hypoxic stimulation also increased the hepatocyte growth factor (HGF) secretion from MRC5 cells, which led to an elevation of c-Met phosphorylation in PK8 cells. Conversely, the elevated cancer invasion, MMP activity and c-Met phosphorylation of PK8 cells were reduced by the removal of HGF from hypoxic conditioned medium. In immunohistochemical study, the HIF-1a expression was observed in surrounding stromal as well as pancreatic cancer cells, thus indicating hypoxia exists in both of cancer and stromal cells. Moreover, the stromal HGF expression was found to significantly correlate with not only the stromal HIF-1a expression but also the c-Met expression in cancer cells. These results indicate that the hypoxic environment within stromal as well as cancer cells activates the HGF/c-Met system, thereby contributing to the aggressive invasive features of pancreatic cancer. ' 2006 Wiley-Liss, Inc.Key words: hypoxia; tumor-stromal interaction; pancreatic cancer; hepatocyte growth factor; c-Met Most aggressive tumors have acquired the ability to develop their own blood vessels as they grow. However, the tumor cells grow faster than the endothelial cells, so the structure and function of the tumor vasculature is highly disorganized in comparison to normal tissues. 1,2 In this microenvironment, within tumor tissues, cancer cells are exposed to hypoxia. 3 Recent studies have revealed that hypoxia-inducible factor-1 (HIF-1) plays a key role in tumor progression under hypoxia. 4,5 HIF-1 is a heterodimeric basic helix-loop-helix PER/ARNT/SIM (HLH-PAS) transcription factor that consists of HIF-1a and a constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT) known as HIF-1b. Under normoxic condition, HIF-1a is bound to the tumor suppressor Von Hippel-Lindau (VHL) protein. This protein complex causes HIF-1a to be targeted by proteasomes, thus leading to rapid protein degradation. Conversely, under hypoxic conditions, HIF-1a is stabilized and dimerized with HIF-1b, translocates to the nucleus and transactivates various gene expressions. HIF-1 is reported to regulate various gene expressions by binding to the hypoxia-responsive element on the target genes. More than 40 genes that are important for glucose transpo...

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Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia

Abstract: Prostatic stromal cells respond to hypoxia by upregulation of secretion of several growth factors suggesting that hypoxia can trigger prostatic growth. Therefore, hypoxia might be a key factor contributing to the pathogenesis of BPH.

Cited by 88 publications

References 41 publications

Hypoxic induction of an HIF-1α–dependent bFGF autocrine loop drives angiogenesis in human endothelial cells

Hypoxic induction of an HIF-1α–dependent bFGF autocrine loop drives angiogenesis in human endothelial cells

Cardiac Vasculature: Development and Pathology

Tumor–stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c‐Met pathway

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